Mitochondria are involved in key cellular processes such as energy supply and calcium buffering critical for neuronal function. It is known that mitochondria are constantly facing various stresses under both physiological and pathological conditions which pose great challenge for the maintenance of mitochondrial homeostasis. As dynamic organelles in cells, mitochondria are continually undergoing fusion and fission to maintain a healthy mitochondrial pool. In addition, mitochondria homeostasis also relies on quality control system of mitochondrial proteostasis. It is well established that mitochondrial chaperones and ATP-dependent proteases form a complex and functionally interconnected system to monitor damaged proteins: mitochondrial chaperones are involved in protein translocation and folding reactions while ATP-dependent proteases are responsible for directly removing misfolded proteins from mitochondria. Increasing evidence demonstrated that defects in mitochondrial protease and chaperones cause mitochondrial dysfunction and have been associated with human diseases especially neurological disorders. In this regard, it is of importance to note that mitochondrial abnormality is an early prominent feature in Alzheimer?s disease (AD) and increasing evidence suggest that mitochondrial dysfunction plays a critical role in the pathogenesis of AD. However, mechanisms underlying mitochondrial dysfunction in AD remain elusive. To explore the potential involvement of an altered mitochondrial quality control system in the pathogenesis of AD, we undertook a pilot study to determine whether there is any change in the expression of mitochondrial chaperones and proteases in AD. Indeed, we found significantly decreased expression of mitochondrial matrix proteases (i.e., CLLP and LONP1) in AD brain tissues. More importantly, ultrastructure analysis of biopsy human brain samples uncovered increased mitochondrial electron dense inclusions, likely aggregations of misfolded proteins, in mitochondria in the susceptible neurons of AD cortex. These data suggested an impaired mitochondrial quality control system in AD. Our in vitro experiments demonstrated that amyloid-beta (A?) inhibits the activity of mitochondrial protease complexes. Interestingly, overexpression of mitochondrial proteases could rescue mitochondrial respiration deficits in primary neuron from CRND8 mice, an APP transgenic mouse model for AD. Based on these exciting preliminary data, we hypothesize that A? induces abnormal mitochondrial proteostasis by impairing the activity of mitochondrial proteases and further causes mitochondrial dysfunction and neuronal loss in AD. To test this hypothesis, we will characterize the causal role of A?-induced abnormal mitochondrial proteostasis in the pathogenesis of AD both in vivo and in vitro which will likely provide novel therapeutic targets of the disease.